The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
It is well known that most, if not all neoplastic diseases are accompanied by a relatively large number of cellular DNA mutations, including point mutations, insertions, deletions, and translocations. Thus, it is reasonable to assume that neoplastic cells should also be characterized by the presence of one or more mutated proteins. Unfortunately, and despite such a simple premise, the search for mutated proteins that are suitable for diagnosis and therapy has been complicated by the fact that different cancer types have different mutated proteins, and worse yet, different patients with the same tumor type have vastly different reservoirs of mutated proteins.
More recently, as a result of numerous research efforts, a relatively small collection of T-cell defined human tumor antigens has become available (see e.g., Cancer Immunity (15 Jul. 2013) Vol. 13, p. 15), however, these antigens have not resulted in a single effective therapeutic agent. Additionally, the use of these antigens in immunotherapy is conceptually questionable, because these antigens are already present in a patient diagnosed with cancer, and should have given rise to an appropriate immune response. Moreover, even if tumor specific antigens are identified and used in a cancer vaccine, the immune response to such antigens may not be sufficiently strong to elicit a therapeutic effect.
All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
In particular, an effective immune therapy requires activated T-cells and activated NK cells to allow specific and rapid destruction of cancer cells. However, while many epitopes associated with or specific to a tumor can be readily processed and even recognized by selected components of the immune system (e.g., by dendritic cells, certain T-cells), a therapeutically effective response by the immune system is often not achieved, possibly due to downregulation of cytotoxic T-lymphocytes and/or NK cells. To counteract downregulation, immune checkpoint inhibitors can be administered to a patient, and some of these therapeutic approaches have shown promise in the clinic (e.g., targeting CTLA-4 or PD-1). However, such approach has not proven universally applicable or even therapeutically effective in most cancers and immune therapy.
The expression of a tumor-associated antigen in genetically engineered T-cells is known. For example, a pox virus has been genetically altered to force infected cells to co-express a tumor associated antigen together with co-stimulatory molecules to so potentially increase an immune response against a tumor carrying the tumor associated antigen (Curr Pharm Des. 2006; 12(3):351-61). However, although co-expression using pox virus was at least conceptually promising, clinical results may be less than desirable as the stimulated immune response could still be reduced by various endogenous factors, and because pox viruses are typically immunogenic and will be eradicated by the patient's immune system.
Thus, while numerous immune therapeutic compositions and methods are known in the art, all or almost all of them suffer from various disadvantages. Therefore, there is still a need for improved compositions and methods that allow for a therapeutically effective immune response in treatment of various cancers.